Failure of the vascular hypothesis of multiple sclerosis in a rat model of chronic cerebrospinal venous insufficiency

Abstract

A b s t r a c t Chronic cerebrospinal venous insufficiency (CCSVI) is a series of stenotic malformations in the cerebrospinal venous outflow routes, which is postulated to cause multiple sclerosis (MS). The hypotheses assumed that CCSVI leads to iron deposition which triggers inflammation and demyelination in MS. Invasive endovascular treatment of CCSVI was initiated based on the previous theory. The present study was designed to validate this hypothesis using a rat model of CCSVI. Bilateral jugular vein ligation (JVL) was performed on female albino rats (n = 15), and sham-operated rats (n = 15) were used as a control group. The rats were followed clinically for eight months and neurological examination detected no weakness or paralysis in the operated

Bilateral jugular veins occlusion in mice: Clinical and histological findings

“…These findings are in part different from those reported in mouse [23] and rat [24] models of chronic bilateral external jugular vein ligation (EJVL), showing no evidence of significant cerebral edema, micro-hemorrages or microglial/macrophage activation. Atkinson et al failed to reveal any evidence of edema, BBB alteration and inflammatory cell infiltration such as activated neutrophils, macrophages, and microglia as measured in vivo with myeloperoxidase-gadolinium (MPOGd) and MRI and in vitro with flow cytometric analysis and immunohistochemitry in the brain and perivascular space of SJL mice studied between 4 and 6 months after JVL.…”

“…In line with previous findings [23][24] we did not find signs of demyelination or major neurological symptoms after surgery.…”

“…Similarly, no microglial/ macrophage nor lymphocytes could be detected in either perivascular or brain parenchymal in JVL rats studied at 8 months after surgery. Interestingly increased activated astrocytes were found at GFAP staining in white matter regions in the EJVL group as compared to the shamoperated group [24]. In addition, these authors also reported marked increase in iron deposition mainly located in white matter tracts within oligodendrocytes and in the endothelial lining of the blood vessels as well as mild brain tissue edema surrounding the mildly enlarged perivascular Virchow Robin spaces in JVL rats.…”

“…The development of animal models of cerebral veins obstructions might contribute to better evaluate and understand the effects of chronic cerebral outflow obstruction on functional, biochemical and morphological alterations of brain tissues. To the best of our knowledge, only two papers described the effect of ligation of neck veins in mice [23,24], but these studies took in consideration only the ligature of the external Jugular veins. Interestingly, a recent study demonstrated that also the internal Jugular vein is an important drainage route for venous flow in mice [25].…”

Brain Venous Blood Outflow

“…Venous outflow has been examined as a potential descriptor of the etiology of various diseases such as migraines, tinnitus, multiple sclerosis, and Alzheimer's disease [1,2]. However, results were often discouraging, with the exception of idiopathic intracranial hypertension, where a model of functional coupling between intracranial pressure (ICP) and sagittal sinus pressure (SSP) has been produced [3].…”